目的非霍奇金淋巴瘤(NHL)在经典霍奇金淋巴瘤(cHL)治疗的患者中作为继发性恶性肿瘤出现是一种罕见且具有挑战性的临床情况。NHL可以与cHL同步呈现,也可以在以后发展,顺序,治疗cHL后长达数年。两种淋巴瘤之间的关系尚不清楚,这些患者的管理没有明确的指南。我们希望对这一问题有更好的临床理解,因此本研究调查了继发性NHL的发生和临床特征。材料和方法在这项回顾性队列检查中,我们收集了在cHL治疗过程中或之后发生NHL的cHL病例。我们对样本进行了组织病理学修订,在样品质量较低的情况下,我们进行了分子检查以发现cHL和NHL之间的关联。我们进行了下一代基因组测序(NGS)和免疫球蛋白重链可变区基因(IgHV)克隆性测试。结果在2011年至2020年诊断的164例cHL患者队列中,6例患者在淋巴瘤复发或进展提示的再活检期间被确定为NHL。其中,5例患者被诊断为生发中心起源的弥漫性大B细胞淋巴瘤(后GCDLBCL),1例患者出现高级别B细胞淋巴瘤(HG-BCL)。NHL的表现在时间上有所不同:成功的cHL治疗后出现了三例,至少有18个月的完全缓解,而其他三名患者则面临原发性难治性cHL。值得注意的是,主要难治性病例没有表现出cHL和NHL之间的确认克隆关系,但NGS数据提出了一种情况下同步NHL的可能性。相比之下,在依次发生NHL的患者中,在一个病例中,IgHV基因的聚合酶链反应(PCR)检测证实了cHL和继发性DLBCL之间的克隆连接,而高度的形态学相似性表明在另一种情况下两种淋巴瘤之间存在潜在的克隆性。结论本研究表明,继发性NHL可能在cHL后同步和依次出现。我们的结果表明,与在诊断时未识别出不同淋巴瘤的序贯病例相比,同步NHL的预后较差。正如我们的数据显示,在某些情况下,在肿瘤细胞克隆进化过程中伴随着它们的突变,后来有额外的突变。在未来,基于下一代测序(NGS)的液体活检样本处理可以克服淋巴恶性肿瘤空间异质性造成的局限性.从长远来看,这种识别可能导致早期患者选择和替代治疗策略,最终导致治疗前景的改善。
Objective Non-Hodgkin lymphoma (NHL) arising as a secondary malignancy in patients treated for classical Hodgkin lymphoma (cHL) is an infrequent and challenging clinical scenario. NHL can be presented synchronously with cHL or may develop later, sequentially, up to years after treatment for cHL. The relationship between the two lymphomas is unclear, and there are no clear guidelines for the management of these patients. We would like to find a better clinical understanding of this issue so this study investigates the occurrence and clinical characteristics of secondary NHL. Materials and methods In this retrospective cohort examination, we collected cHL cases when NHL occurred during or after the course of treating cHL. We performed the histopathologic revisions of the samples, and in every case where the quality of the sample was lower, we performed molecular examinations to find the association between cHL and NHL. We performed next-generation genome sequencing (NGS) and immunoglobulin heavy-chain variable region gene (IgHV) clonality testing. Results In a cohort of 164 cHL patients diagnosed between 2011 and 2020, six patients were identified with NHL during rebiopsy prompted by lymphoma relapse or progression. Among these, five patients were diagnosed with post-germinal center-originated diffuse large B-cell lymphoma (post-GC DLBCL), and one patient presented high-grade B-cell lymphoma (HG-BCL). The NHL manifestation differed in its timing: three cases emerged after successful cHL treatment, with at least 18 months of complete remission, while the other three patients faced primary refractory cHL. Notably, the primary refractory cases did not exhibit a confirmed clonal relationship between cHL and NHL, but NGS data raised the possibility of synchronous NHL in one case. In contrast, among the patients with sequentially occurring NHL, polymerase chain reaction (PCR) testing of the IgHV gene affirmed a clonal connection between cHL and secondary DLBCL in one case, while the high morphological similarity suggested a potential clonality between the two lymphomas in another case. Conclusion This study reveals that secondary NHL may manifest both synchronously and sequentially following cHL. Our results suggest that synchronous NHL has a worse prognosis compared to sequential cases when the different lymphomas are not recognized at the time of diagnosis. As our data showed, in some cases, mutations that accompany the tumor cells throughout their clonal evolution can be identified, with additional mutations later on. In the future, next-generation sequencing (NGS)-based processing of liquid biopsy samples can overcome the limitations resulting from the spatial heterogeneity of lymphoid malignancies. Over the long term, this identification could lead to early patient selection and alternative treatment strategies, ultimately leading to improved prospects for cure.